The global burden of HIV in adolescent girls is significant, accounting for 22% of all new infections. This population is also heavily impacted by often-unintended pregnancies accounting for approximately 11% of all births worldwide. Therefore, safe and effective contraceptives which does not increase risks of HIV acquisition and transmission needs to be urgently evaluated in this population. Progestin based contraceptive DMPA have been found to be associated with enhanced HIV acquisition/transmission in adult women. However, effects in adolescents have not been evaluated. Existing data indicates adolescent genital immune microenvironment to be distinct and characterized by high baseline inflammation and presence of cervical ectopy which might be conducive to enhanced HIV susceptibility. It is currently unknown whether continued usage of progestin-based contraceptives can further enhance HIV susceptibility in this population. The overall objective of this proposal is to evaluate the biological impact of continued use of three types of progestin-based contraceptives, levonorgestrel intrauterine device (LNG-IUD), subdermal etonogestrel (ETNG), and Depot medroxyprogesterone acetate (DMPA), on the inflammatory and microbiologic environment in the genital tract of adolescent girls. We propose a longitudinal study to evaluate immune microenvironment in the genital tract in fifty sexually active, HIV negative adolescent girls aged 15-19 before and after using progestin-based contraceptives and compare with girls using combined oral contraceptives (estrogen and progesterone) or condoms-only. Our central hypothesis is that continued usage of progestin-based contraceptives will compromise immune protection in adolescent genital tract. This proposal focuses on HIV risks in adolescent girls, a priority population for NIH. Assessment of data proposed in this study will alert the medical community of to date unexplored risks and a comparison of progestin-based contraceptive use. This will spur further research and lead to well-informed recommendations for contraceptive choices that may improve overall reproductive health in adolescent girls.